White Matter Myelination Research Articles

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease.

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.

Neuro-hepatopathological changes in juvenile Oreochromis niloticus exposed to sublethal concentrations of commercial herbicides

The current study estimates the impact of different common herbicides on antioxidant defenses and histological structure of liver and spinal cord of juvenile tilapia. Eighty-four fish were divided into seven groups: group 1 fish acted as controls and the remaining fish were exposed to sublethal concentrations of acetochlor, bispyribac-sodium, bentazon, bensulfuron-methyl, halosulfuron-methyl, or quinclorac at sublethal concentrations 2.625, 0.800, 36.00, 2.50, 1.275, and 11.250 mg/l, respectively, for 96 h. Antioxidant parameters changed in response to some test herbicides and the greatest effects were caused by exposure to acetochlor and quinelorac for all antioxidant measurements. Prominent histological changes in liver tissue included loss of liver architecture and the appearance of fatty liver cells, necrotic areas, foci of leukocytic infiltration and many apoptotic cells. The most obvious changes in the spinal cord in all treated fish were degradation of myelinated white matter fibers with the emergence of empty spaces, large aggregation of pyknotic neuroglial nuclei, and damaged areas in the dorsal horn of gray matter. Collectively, the harmful effect of tested herbicides on antioxidant capacity and significant alterations in histological structures of liver and spinal cord of Oreochromis niloticus.

Altered myelination in youth born with congenital heart disease.

Brain injury and dysmaturation is common in fetuses and neonates with congenital heart disease (CHD) and is hypothesized to result in persistent myelination deficits. This study aimed to quantify and compare myelin content in vivo between youth born with CHD and healthy controls. Youth aged 16 to 24 years born with CHD and healthy age‐ and sex‐matched controls underwent brain magnetic resonance imaging including multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). Average myelin water fraction (MWF) values for 33 white matter tracts, as well as a summary measure of average white matter MWF, the White Matter Myelination Index, were calculated and compared between groups. Tract‐average MWF was lower throughout the corpus callosum and in many bilateral association tracts and left hemispheric projection tracts in youth with CHD (N = 44) as compared to controls (N = 45). The White Matter Myelination Index was also lower in the CHD group. As such, this study provides specific evidence of widespread myelination deficits in youth with CHD, likely representing a long‐lasting consequence of early‐life brain dysmaturation in this population. This deficient myelination may underlie the frequent neurodevelopmental impairments experienced by CHD survivors and could eventually serve as a biomarker of neuropsychological function.

Analysis of clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion

Objective: To investigate the clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion. Methods: The patients (n=10) with 16p11.2 microdeletion found in children with epilepsy treated in Beijing Children's Hospital Affiliated to Capital Medical University from January 2018 to January 2021 were collected. The clinical manifestations, gene variations and prognosis were analyzed retrospectively. Results: A total of 10 children's data were collected, including 5 male and 5 female. The onset age of epilepsy was 4.5 (4.1,5.0) months. Regarding the seizure types, 7 cases had focal seizures with secondary generalization, 2 cases had generalized seizures, and 1 case had tonic seizures and spasms. Nine cases had cluster seizure attacks and 3 cases had status epilepticus. Seven cases had focal or multifocal epileptiform discharges in interictal electroencephalogram (EEG), 3 cases had borderline or normal EEG. Brain magnetic resonance imaging showed polymicrogyria in 1 case, paraventricular leukomalacia in 1 case, delayed myelination of white matter in 3 cases, and no obvious abnormalities in the other 5 cases. The patients were followed up for 0.5-3.5 years, with 1-3 kinds of antiepileptic drugs taken orally. The case with polymicrogyria still had seizures, however the other 9 cases had seizures controlled. The age of the last seizure attack was 8 (6, 12) months. There were 6 cases with mental and motor developmental delay before epilepsy onset. During the follow-up, 7 cases were retarded to varying degrees, while 3 cases had normal development. Regarding the genetic detection methods, 7 cases underwent whole exome sequencing, 2 cases underwent whole genome copy number variation detection, and 1 case underwent whole genome sequencing. The length of the 16p11.2 deletion in 10 cases ranged from 525 to 951 kb, and all contained the PRRT2 gene intact. Six cases were de novo variants, 1 case was inherited from the mother who had a history of convulsions in early childhood, and the source of variant was not verified in 3 cases, none of whose parents had relevant phenotype. Conclusions: The epilepsy associated with 16p11.2 microdeletion is mainly induced by the heterozygous deletion of PRRT2 gene in this region, however the phenotype is usually severe, and often combined with developmental and epileptic encephalopathy. Detection of copy number variation should be emphasized in children whose etiology is considered genetic but second-generation sequencing result is negative.

DHF-7 Ameliorates Behavioral Disorders and White Matter Lesions by Regulating BDNF and Fyn in a Mouse Model of Schizophrenia Induced by Cuprizone and MK-801.

BackgroundSchizophrenia is a psychiatric disorder including multiple clinical symptoms such as severe psychosis and cognitive dysfunction. DHF-7 is a novel dihydroflavanone derivative that was designed and synthesized to treat schizophrenia. This study aimed to investigate the effects and mechanisms of DHF-7 in a mouse model of schizophrenia induced by a combination of cuprizone and MK-801.MethodsAfter intragastric administration of DHF-7 for 7 weeks, open field, Y-maze, and novel object recognition tests were performed to detect behavioral changes in the mouse model. White matter lesions and myelin loss were determined using transmission electron microscopy and oil red O staining. Western blotting and immunohistochemistry were used to detect the expression of the related proteins.ResultsThe results showed that DHF-7 treatment significantly improved cognitive impairment and positive symptoms in the model mice. Moreover, DHF-7 alleviated white matter lesions and demyelination and promoted the differentiation and maturation of oligodendrocytes for remyelination in the corpus callosum of model mice. The mechanistic study showed that DHF-7 increased the expression of brain-derived neurotrophic factor and phosphorylated Fyn, thus activating the tyrosine kinase receptor B (Trk B)/Fyn/N-methyl-D-aspartate receptor subunit 2 B (NMDAR2B) and Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-related kinase (ERK) signaling pathways.ConclusionsOur results provide an experimental basis for the development of DHF-7 as a novel therapeutic agent for schizophrenia.

Orientation dependence of inhomogeneous magnetization transfer and dipolar order relaxation rate in phospholipid bilayers

Inhomogeneous magnetization transfer (ihMT) is a novel MRI technique used to measure white matter myelination in the brain and spinal cord. In the brain, ihMT has a strong orientation dependence which is likely to arise from the anisotropy of dipolar couplings between protons on oriented lipids in the myelin bilayers. We measured the orientation dependence of the second moment (M2) of the lineshape, dipolar order relaxation rate (R1D), and ihMT ratio (ihMTR) in an oriented phospholipid bilayer at 9.4 T. We found a strong orientation dependence in all three parameters. ihMTR and R1D were maximized when the bilayers were aligned perpendicular to B0 and minimized near the magic angle (∼54.7°). M2 followed an orientation dependence given by the second Legendre polynomial squared as predicted by the form of the secular dipolar Hamiltonian. These results were used to calculate the orientation dependence of R1D and ihMTR in a diffusionless myelin sheath model, which showed ihMTR was maximised for fibers perpendicular to B0 and minimised at 45°, similar to ex-vivo spinal cord with a larger prepulse frequency offset, but in contrast to in vivo brain findings. Adding fiber dispersion to this model smoothed the orientation dependence curve as expected. Our results suggest the importance of the effects of lipid diffusion and prepulse offset frequency on ihMTR.

Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants.

ObjectiveThis study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine.MethodsThrough a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software.ResultsIn 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam.ConclusionThe clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management.

For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.

White matter myelination during early infancy is linked to spatial gradients and myelin content at birth

Development of myelin, a fatty sheath that insulates nerve fibers, is critical for brain function. Myelination during infancy has been studied with histology, but postmortem data cannot evaluate the longitudinal trajectory of white matter development. Here, we obtained longitudinal diffusion MRI and quantitative MRI measures of longitudinal relaxation rate (R1) of white matter in 0, 3 and 6 months-old human infants, and developed an automated method to identify white matter bundles and quantify their properties in each infant’s brain. We find that R1 increases from newborns to 6-months-olds in all bundles. R1 development is nonuniform: there is faster development in white matter that is less mature in newborns, and development rate increases along inferior-to-superior as well as anterior-to-posterior spatial gradients. As R1 is linearly related to myelin fraction in white matter bundles, these findings open new avenues to elucidate typical and atypical white matter myelination in early infancy.

JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory Tcell induction.

Dendritic cells (DCs) induce peripheral Tcell tolerance, but cell-intrinsic signaling cascades governing their stable tolerogenesis remain poorly defined. Janus Kinase 1 (JAK1) transduces cytokine-receptor signaling, and JAK inhibitors (Jakinibs), including JAK1-specific filgotinib, break inflammatory cycles in autoimmunity. Here, we report in heterogeneous DC populations of multiple secondary lymphoid organs that JAK1 promotes peripheral Tcell tolerance during experimental autoimmune encephalomyelitis (EAE). Mice harboring DC-specific JAK1 deletion exhibit elevated peripheral CD4+ Tcell expansion, less regulatory Tcells (Tregs), and worse EAE outcomes, whereas adoptive DC transfer ameliorates EAE pathogenesis by inducing peripheral Tregs, programmed cell death ligand 1 (PD-L1) dependently. This tolerogenic program is substantially reduced upon the transfer of JAK1-deficient DCs. DC-intrinsic IFN-γ-JAK1-STAT1 signaling induces PD-L1, which is required for DCs to convert CD4+ Tcells into Tregs invitro and attenuated upon JAK1 deficiency and filgotinib treatment. Thus, DC-intrinsic JAK1 promotes peripheral tolerance, suggesting potential unwarranted DC-mediated effects of Jakinibs in autoimmune diseases.

Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury

Clinical trials of therapeutics for traumatic brain injury (TBI) demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, in part due to the absence of clinically feasible therapeutic windows for administration. Minocycline, an inhibitor of microglial activation, has been shown to be neuroprotective when administered early after experimental TBI but detrimental when administered chronically to human TBI survivors. Rather than focusing on the rescue of primary injury with early administration of therapeutics which may not be clinically feasible, we hypothesized that minocycline administered at a clinically feasible time point (24 h after injury) would be neuroprotective in a model of TBI plus delayed hypoxemia. We first explored several different regimens of minocycline dosing with the initial dose 24 h after injury and 2 h prior to hypoxemia, utilizing short-term neuropathology to select the most promising candidate. We found that a short course of minocycline reduced acute microglial activation, monocyte infiltration and hippocampal neuronal loss at 1 week post injury. We then conducted a preclinical trial to assess the long-term efficacy of a short course of minocycline finding reductions in hippocampal neurodegeneration and synapse loss, preservation of white matter myelination, and improvements in fear memory performance at 6 months after injury. Timing in relation to injury and duration of minocycline treatment and its impact on neuroinflammatory response may be responsible for extensive neuroprotection observed in our studies.

Клінічний випадок природженої CMV-нейроінфекції в дитини з вибірковим дефіцитом IgA

Вважають, що природжена CMV-інфекція має місце щонайменше у 1 % немовлят, хоча результати останніх клінічних досліджень вказують на питому вагу зазначених уражень на рівні 8 % випадків серед усіх новонароджених. Тяжкість клінічних симптомів ураження нервової системи CMV-етіології залежить від терміну внутрішньоутробного інфікування. При ранньому інфікуванні, протягом першого триместру внутрішньоутробного періоду, коли відбувається закладка головного мозку, розвиваються тяжкі вади центральної нервової системи, включаючи аненцефалію, поренцефалію, шизенцефалію, лісенцефалію, мікрополігірію та пахігірію. При більш пізньому зараженні, протягом 2–3-го триместру вагітності, відзначають більш легкі прояви: вентрикуломегалію, порушення мієлінізації білої речовини мозку, кісти в полюсах скроневих часток, гіпогенезію мозолистого тіла, перивентрикулярні кальцифікати та ураження кохлеовестибулярних нервів. В статті наведено історію хвороби хлопчика віком 5 років з типовими клініко-інструментальними ознаками природженої CMV-інфекції. У дитини відзначались глибокий спастичний тетрапарез, тяжка затримка психомовленнєвого розвитку, рефрактерний епілептичний синдром із поліморфними нападами, порушення роботи тазових органів, унеможливлення самостійного пересування. МРТ головного мозку демонструвала типові радіологічні ознаки природженої CMV-інфекції: кортикальну атрофію, вентрикуломегалію, перивентрикулярний гліоз, поля демієлінізації в білій речовині півкуль, кісти в полюсах скроневих часток, гіпоплазію мозолистого тіла. Протягом періоду новонародженості відзначалися специфічні IgM до СMV у сироватці крові. ПЛР лейкоцитів крові виявила ДНК СMV у дитини в 5-річному віці на момент звернення в клініку за медичною допомогою. Ця інфекція призводила до генералізованої лімфаденопатії, гепатоспленомегалії, тромбоцитопенії та лімфомоноцитозу. Оцінка імунного статусу показала наявність вибіркового дефіциту IgA, з чим пов’язали розвиток цієї опортуністичної інфекції. Обговорені типові помилки при клінічному веденні дітей із природженою CMV-інфекцією та шляхи їх уникнення.

Therapeutic Effects of Myriocin in Experimental Alcohol-Related Neurobehavioral Dysfunction and Frontal Lobe White Matter Biochemical Pathology.

Chronic excessive alcohol consumption causes white matter degeneration with myelin loss and impaired neuronal conductivity. Subsequent rarefaction of myelin accounts for the sustained deficits in cognition, learning, and memory. Correspondingly, chronic heavy or repeated binge alcohol exposures in humans and experimental models alter myelin lipid composition leading to build-up of ceramides which can be neurotoxic and broadly inhibitory to brain functions. This study examined the effects of chronic + binge alcohol exposures (8 weeks) and intervention with myriocin, a ceramide inhibitor, on neurobehavioral functions (Open Field, Novel Object Recognition, and Morris Water Maze tests) and frontal lobe white matter myelin lipid biochemical pathology in an adult Long-Evans rat model. The ethanol-exposed group had significant deficits in executive functions with increased indices of anxiety and impairments in spatial learning acquisition. Myriocin partially remediated these effects of ethanol while not impacting behavior in the control group. Ethanol-fed rats had significantly smaller brains with broadly reduced expression of sulfatides and reduced expression of two of the three sphingomyelins detected in frontal white matter. Myriocin partially resolved these effects corresponding with improvements in neurobehavioral function. Therapeutic strategies that support cerebral white matter myelin expression of sulfatide and sphingomyelin may help remediate cognitive-behavioral dysfunction following chronic heavy alcohol consumption in humans.

Artificial Intelligence-based Myelinated White Matter Segmentation for a Pediatric Brain - A Challenging Task

Background: Segmentation of a baby brain,in particular myelinated white matter is a very challenging and important task in medical image analysis, because of the ongoing process of myelination and structural differences present in magnetic resonance images of a baby. Most available algorithms for segmentation of a baby brain are atlas based segmentations, which may not accurate because baby brain Magnetic Resonance Images (MRI) are very subjective. Objective: Artificial intelligence based methods for myelinated white matter segmentation. Method: Fuzzy C-means Clustering with Level Set Method (FCMLSM), Adaptively Regularized Kernel-based Fuzzy C-means clustering (ARKFCM), Multiplicative Intrinsic Component Optimization (MICO) and Particle Swarm Optimization (PSO). Results: Signal to Noise Ratio (SNR), Edge Preservation Index (EPI), Structural Similarity Index (SSIM) and Peak Signal to noise Ratio (PSNR) Accuracy, Precision, Dice and Jaccard values are maintained good and Mean squared error (MSE) is less for FCMLSM. Conclusion: FCMLSM is a very suitable method for myelinated white matter segmentation when compared to ARKFCM, MICO and PSO.

Association between gray/white matter contrast and white matter microstructural alterations in medication-naïve obsessive–compulsive disorder

Intracortical myelin is involved in speeding and synchronizing neural activity of the cerebral cortex and has been found to be disrupted in various psychiatric disorders. However, its role in obsessive–compulsive disorder (OCD) has remained unknown. In this study, we investigated the alterations in intracortical myelin and their association with white matter (WM) microstructural abnormalities in OCD. T1-weighted and diffusion-weighted brain images were obtained for 51 medication-naïve patients with OCD and 26 healthy controls (HCs). The grey/white matter contrast (GWC) was calculated from T1-weighted signal intensities to characterize the intracortical myelin profile in OCD. Diffusion parameters, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), were extracted from diffusion-weighted images to examine the WM microstructure in OCD. Compared with HCs, patients with OCD showed increased GWC in the bilateral orbitofrontal, cuneus, lingual and fusiform gyrus, left anterior cingulate, left superior parietal, right inferior parietal, and right middle frontal cortices, suggesting reduced intracortical myelin. Patients with OCD also showed decreased FA in several WM regions, with a topology corresponding to the GWC alterations. In both groups, the mean GWC of the significant clusters in between-group GWC analysis was correlated negatively with the mean FA of the significant clusters in between-group FA analysis. In patients with OCD, the FA of a cluster in the right cerebellum correlated negatively with the Yale-Brown obsessive–compulsive scale scores. Our results suggest that abnormal intracortical and WM myelination could be the microstructural basis for the brain connectivity alterations and disrupted inhibitory control in OCD.

Sustained Energy Deficit Following Perinatal Asphyxia: A Shift towards the Fructose-2,6-bisphosphatase (TIGAR)-Dependent Pentose Phosphate Pathway and Postnatal Development.

Labor and delivery entail a complex and sequential metabolic and physiologic cascade, culminating in most circumstances in successful childbirth, although delivery can be a risky episode if oxygen supply is interrupted, resulting in perinatal asphyxia (PA). PA causes an energy failure, leading to cell dysfunction and death if re-oxygenation is not promptly restored. PA is associated with long-term effects, challenging the ability of the brain to cope with stressors occurring along with life. We review here relevant targets responsible for metabolic cascades linked to neurodevelopmental impairments, that we have identified with a model of global PA in rats. Severe PA induces a sustained effect on redox homeostasis, increasing oxidative stress, decreasing metabolic and tissue antioxidant capacity in vulnerable brain regions, which remains weeks after the insult. Catalase activity is decreased in mesencephalon and hippocampus from PA-exposed (AS), compared to control neonates (CS), in parallel with increased cleaved caspase-3 levels, associated with decreased glutathione reductase and glutathione peroxidase activity, a shift towards the TIGAR-dependent pentose phosphate pathway, and delayed calpain-dependent cell death. The brain damage continues long after the re-oxygenation period, extending for weeks after PA, affecting neurons and glial cells, including myelination in grey and white matter. The resulting vulnerability was investigated with organotypic cultures built from AS and CS rat newborns, showing that substantia nigra TH-dopamine-positive cells from AS were more vulnerable to 1 mM of H2O2 than those from CS animals. Several therapeutic strategies are discussed, including hypothermia; N-acetylcysteine; memantine; nicotinamide, and intranasally administered mesenchymal stem cell secretomes, promising clinical translation.

An autopsy case of adult‐onset neuronal intranuclear inclusion disease with perivascular preservation in cerebral white matter

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by appearance of eosinophilic hyaline intranuclear inclusions. While the main symptoms of adult-onset NIID are dementia or limb weakness, some patients present with encephalitic episodes and transient neurological symptoms. The pathophysiology of these acute, transient symptoms, however, remains unknown. Here, we describe an autopsy case of adult-onset NIID with progressive dementia and transient hemiparesis. The patient was a 70-year-old man without a relevant family history, and initially presented with progressive dementia. He then exhibited transient left hemiparesis at 75 years of age and died of ureteral cancer at 77 years of age. Neuropathological examination revealed the presence of multiple areas of focal spongiosis in the subcortical white matter and patchy myelin pallor of the white matter, as in previous reports. However, perivascular areas were preserved even in the damaged white matter. In addition, dense glial fibrillary acidic protein (GFAP)-immunoreactive astrocytic processes were observed in these areas. [Correction added on 23 January 2022, after first online publication: the preceding sentence has been corrected to improve readability.] GFAP immunohistochemistry revealed decreased density and morphological abnormalities of astrocytes in the affected white matter. These pathological findings might reflect blood-brain barrier impairment and dysregulation of blood flow, which may be related to the pathophysiology of the acute, transient symptoms observed in NIID.

Higher myelination of grey matter and white matter is associated with lower tau spreading and tau‐associated cortical thinning in Alzheimer’s

AbstractBackgroundMyelination of axons in the grey matter (GM) and axonal connections may modulate the spreading of brain pathologies such as pathologic tau. Here, we tested for the first time whether MRI‐assessed myelination in the GM and white matter (WM) is associated with tau‐PET assessed spreading of pathologic tau between connected brain regions. We hypothesized that 1) higher myelination of WM connections is associated with lower tau‐PET in the connected regions and 2) higher myelination of GM is associated with higher resilience against the effect of tau on GM.MethodWe included AV1451‐tau‐PET from 202 amyloid‐PET positive (Aβ+) asymptomatic and symptomatic individuals from ADNI. Using a neocortical 200‐ROI brain‐parcellation atlas, we obtained regional tau‐PET SUVR and cortical thickness. Resting‐state fMRI functional connectivity (FC) and DWI‐based fiber‐tracts between the 200 ROIs were assessed in 100 individuals from the human connectome project (HCP). Next, we applied the 200 GM‐ROIs and fiber‐tract streamlines to a myelin‐water‐imaging atlas in healthy individuals (Liu et al., JON, 2019) to assess the myelin water fraction (MWF) in GM‐ROIs and their WM connections. Using linear regression, we assessed the associations between MWF, FC and tau‐PET, as well as the interaction between MWF and tau‐PET on cortical thickness.ResultWe found that higher MWF (i.e. higher myelin) in GM‐ROIs was associated with lower tau‐PET in corresponding ROIs (Figure 1, β=‐0.38, p<0.001). Using spatial regression, we found that for connections with lower MWF, the association between higher FC and higher tau‐PET was stronger (interaction MWF x FC on tau‐PET, Figure 2), suggesting that lower WM myelination facilitates the spreading of tau along connected regions. Lastly, the association between tau‐PET and cortical thinning in GM‐ROIs was attenuated at higher MWF in the corresponding GM‐ROIs (Figure 3, β=0.025, p<0.001), suggesting that higher GM myelination is associated with higher resilience against the effect of tau‐PET on GM atrophy.ConclusionHigher myelination of the GM and WM is associated with lower regional susceptibility to pathologic tau and higher resilience against effects of tau on GM integrity.

Alterations in white matter integrity in cognitively stable Down syndrome correlate with plasma neurofilament light chain: Evidence of early myelin breakdown

AbstractBackgroundAlterations in white matter (WM) integrity occur in adults with DS during the early stage of dementia. These changes may be documented by diffusion tensor imaging wherein increases in radial diffusivity (RD), a marker of dysmyelination or myelin breakdown, occur in commissural and limbic pathways in DS. Neurofilament light chain (NfL) is a support protein within large, myelinated axons specifically within the cerebral white matter and is released into blood following axonal damage and is increased in DS. In this study, we evaluated the association between plasma NfL concentrations and RD.MethodThirty cognitively stable adults with DS from the Alzheimer Disease in Down Syndrome (part of the ABC‐DS) study, (18 M, 12 F: mean age 47.1 years SD 5.2 years), underwent DTI and plasma NfL concentration measurements. Plasma NfL was assayed using the Simoa platform. Diffusion MRI connectometry was conducted using q‐space diffeomorphic reconstruction and a multiple regression model to assess the associations between plasma NfL and white matter radial diffusivity (RD). The Spearman correlation coefficient, and its 95% confidence interval (CI), was used to quantify the monotonic association between plasma NfL and RD.ResultConsistent with our hypothesis, we found positive associations between plasma NfL and RD increases, in several WM higher order association tracts, including the corpus callosum (0.46, 95% CI 0.11‐0.70, p=0.012), the cingulum bundle (L: 0.62, 0.34‐0.80, p<0.001; R: 0.54 0.23‐0.76, p=0.002) and the uncinate fasciculus (L: 0.17, ‐0.20‐0.50, p=0.367; R: 0.51, 0.18‐0.73, p=0.004).ConclusionOur findings support an important link between alterations in WM myelin integrity, particularly of higher order association areas, and axonal degeneration in cognitively stable adults with Down syndrome. These findings support an important role of WM alterations in adults with DS who are at risk for and who develop AD earlier than in sporadic AD cases. WM might provide an important and novel target for intervention. Additional research is needed to understand the underlying neuropathological processes, including the potential contribution of neuronal dysfunction and/or loss to our findings. Acknowledgements: NIH grant U01AG051412. We are grateful to our participants, families, the agencies serving individuals with ID, and our dedicated staff.

Insights into human cerebral white matter maturation and degeneration across the adult lifespan

White matter (WM) microstructural properties change across the adult lifespan and with neuronal diseases. Understanding microstructural changes due to aging is paramount to distinguish them from neuropathological changes. Conducted on a large cohort of 147 cognitively unimpaired subjects, spanning a wide age range of 21 to 94 years, our study evaluated sex- and age-related differences in WM microstructure. Specifically, we used diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) indices, sensitive measures of myelin and axonal density in WM, and myelin water fraction (MWF), a measure of the fraction of the signal of water trapped within the myelin sheets, to probe these differences. Furthermore, we examined regional correlations between MWF and DTI indices to evaluate whether the DTI metrics provide information complementary to MWF. While sexual dimorphism was, overall, nonsignificant, we observed region-dependent differences in MWF, that is, myelin content, and axonal density with age and found that both exhibit nonlinear, but distinct, associations with age. Furthermore, DTI indices were moderately correlated with MWF, indicating their good sensitivity to myelin content as well as to other constituents of WM tissue such as axonal density. The microstructural differences captured by our MRI metrics, along with their weak to moderate associations with MWF, strongly indicate the potential value of combining these outcome measures in a multiparametric approach. Furthermore, our results support the last-in-first-out and the gain-predicts-loss hypotheses of WM maturation and degeneration. Indeed, our results indicate that the posterior WM regions are spared from neurodegeneration as compared to anterior regions, while WM myelination follows a temporally symmetric time course across the adult life span.